The female sex hormones estrone and estradiol are involved in many physiological processes and have been studied extensively. The formation of these steroids is regulated by a number of enzymes. The enzyme aromatase is the rate limiting enzyme in the conversion of testosterone and androstenedione (male hormones, androgens) to estradiol and estrone (female hormones, estrogens). The non-reversible conversion of these androgens to the estrogens involves the oxidation and elimination of the methyl groups at C-10 as formic acid. The 1.beta.- and 2.beta.-hydrogens from C-1 and C-2 are lost with the formation of a double bond so that, after enolization of the 3-ketone, the aromatic A-ring of the estrogens is produced. The androgens, testosterone and androstenedione, can be interconverted by 17.beta.-hydroxy-steroid dehydrogenase and the estrogens, estradiol and estrone, can be interconverted similarly (Scheme 1). Materials, such as aromatase inhibitors that regulate the androgen to estrogen conversion or inhibit this conversion have therapeutic utility in treating clinical conditions which are potentiated by the presence of the estrogens. Such aromatase inhibitors have been identified using microsomal enzyme preparations from human placenta and 4-hydroxy- and 4-acetoxy-androst-4-ene-3,17-dione, androsta-1,4,6- triene-3,17-dione, aminoglutethimide and testololactone have been identified as aromatase inhibitors. ##STR2##
The conditions being treated with aromatase inhibitors can involve elevated levels of estrogens which are essentially steady or which may only be temporary surges resulting from cyclical body functions. Thus, aromatase inhibitors have been used for treatment of hyperestrogenemia in conditions such as gynecomastia and clinical improvement has resulted. They have also been used succesfully in treating male infertility associated with oligospermia which results from elevated estrogen levels. Aromatase inhibitors can also be used in treating hyperestrogenemia which may precede myocardial infarction.
Aromatase inhibitors are also useful in fertility control where they would be effective by reducing the estrogen surges observed at various stages of the ovulatory cycle. Thus, 4-acetoxyandrost-4-ene-3,17-dione has been found effective in preventing estrogen production required for ovulation in rats. In addition, since estrogen synthesis is necessary for implantation of fertilized ova in many species, post-coital administration of aromatase inhibitors has the potential to regulate fertility, particularly in domestic pets and wildlife. In particular, the aromatase inhibitor androsta-1,4,6-triene-3,17-dione has been found effective in preventing implantation in mated rats. Aromatase inhibitors should also reduce mating behavior of male species which require brain aromatization for such behavior. In particular, suppression of rodent reproduction has been effective by using aromatase inhibitors in the treatment of males and females during controlled mating programs.
There is also substantial clinical evidence to indicate that many tumor types are associated with elevated estrogen production. Ovariectomy, adrenalectomy and hypophysectomy are commonly employed in patients with breast cancer as a means of reducing the amount of estrogen. Non-surgical procedures include treatments with high levels of steroids, anti-estrogens and inhibitors of steroidal enzymatic pathways. Treatment with antiestrogens results in about one-third of the patients obtaining objective tumor regressions. Andrenalectomy will cause regression of breast cancer in postmenopausal women with hormonal-dependent tumors, presumably as the result of reduction in available estrogen derived from androstenedione, whose source is primarily from the adrenals. Growth of several lines of breast cancer cells have been shown to be estrogen-dependent, and can be inhibited by compounds which antagonize estrogen action.
Thus, aromatase, inhibitors such as those named earlier, can effectively prevent the biologically active estrogens from reaching endrocrine tumors or reduce estrogen biosynthesis in those tumors capable of endogenous estrogen synthesis, thereby producing remissions of metastatic breast cancer.
Endometrial cancer has been related to the presence of excessive endogenous or exogenous estrogen. Gonadal and trophoblastic tumors cause somatic hyperestrogenization, which results in varying degrees of feminization in males. In females, the symptoms depend upon the age of the patient, and may range from precocious pseudopuberty to abnormalities of menses to postmenopausal bleeding. Aromatase inhibitors can be used in adjunctive therapy in the conservative management of patients with such tumors, since they will reduce the somatic expression of increased estrogen biosynthesis.